The goal of this proposal is the development of metabolically stable, orally active, nonaddicting opioid peptide analgesics. The strategy chosen is the synthesis of opioid peptides possessing (a) modified backbones that are not susceptible to peptidase degradation and (b) M tyrosine or Beta-CH3 m tyrosine residues, modifications known to increase antagonist activity and Mu-selectivity of enkephalin analogs. A series of enkephalin and morphiceptin types of opioid peptides with potential mixed agonist/antagonist activity will be synthesized. Receptor selectivities and affinities will be determined by competitive inhibition studies using multiple labeled ligands and computer-assisted analysis of multiple-site models. Agonist and antagonist activity and their duration of action in the tail flick test after intracerebroventricular, intravenous, and oral administration will be determined. The physical-dependence liability of promising analogs will be assessed in collaboration with the Committee on Problems of Drug Dependence. In a parallel effort, molecular modeling studies will be done for all candidate peptides to identify and calculate reliable molecular criteria for high-affinity Mu-receptor binding and agonist and antagonist activity, and to help select promising analogs for synthesis. Among the properties to be calculated will be energy-conformation profiles, including geometry relaxation, entropy and solvent effects, and molecular electrostatic potentials. Pharmacophore mapping of these properties will be done to obtain candidate Mu-selective agonist and antagonist pharmacophores and to model receptor interactions with these pharmacophores. If successful, these combined efforts will yield orally active opioid analgesics with little or no physical-dependence liability, eliminating the current need for intravenous administration of such drugs and lowering the risk of addiction.